A summary of our findings is briefly made. A functional examination of the kidneys did not allow any differentiation between the results of vascular and parenchymal damage. This was true, as is emphasized in the arrangement of Charts 1 and 2, in the case of both glomerular and tubular dysfunction for it is seen that the type of functional derangement is identical in the two types of damage. Anatomical examination of the kidneys on the other hand showed definite differences in the state of the kidneys in the two types of damage, whether the dysfunction was glomerular or tubular.

Certain points should be emphasized here. First, the validity of these results is not dependent on any particular interpretation of the significance of the functional phenomena observed. Whatever the anatomical relations between the two circulations in the kidney, whether urea, salts, dyes or water is excreted by one mechanism or another, no matter what part "filtration" or "absorption" may play in the elaboration of the final urine, the fact remains that the status of the function of these kidneys was identical, no matter how its functional state came into being, when an anatomical examination showed their actual condition to be significantly different.

The fact that vascular disturbances, if of sufficient duration may in turn produce parenchymal changes complicates the problem still further, for in lesions that spontaneously develop in the kidney the mixture of vascular and parenchymal disturbances is so intimate that the functional results become infinitely more difficult of interpretation. Our previous studies have shown that even in the controlled extravital experiment conditions and relations of functional and structural response may thus become exceedingly complex (2). These complications were purposely avoided in the present study, however, by making the period of vascular disturbance short. Also, and again for the purpose of simplification, the toxic agent which caused the parenchymal disturbances was used in low enough concentration to produce only the less complex of the structural alterations that may follow its contact with the cells. And for the same reasons the simplicity of the general conditions existing in the perfusion experiments deserves special emphasis. Every element of the circulating fluid that is going to the kidneys is known and may be varied at will. Every constituent of the urine formed from this fluid can be accurately determined and compared with its condition in the circulating fluid. We have given in our experiments only rates of excretion but "concentration factors," "ratios," "clearances" or any other formulae might be calculated, without altering the conclusion that the functional status of the organs in the two types of damage, vascular and parenchymal, was identical.

All these contrasts between the simplicity of our experiments and the complexity that must obtain when the problem is investigated in the living animal, particularly if mammals are used whose renal activity is only partially understood, add considerable weight to the conclusion that functional examination is unable to differentiate between two types of damage of very different significance, the one vascular, transient and reversible, the other parenchymal, permanent and, as far as the cells involved are concerned, irreparable.

It might seem that a similar result is the proper conclusion to be drawn from the long series of similar attempts by clinical and experimental study to determine the condition of the kidneys from functional examinations. But it has been and apparently still is hoped, perhaps because in such examinations relations are so complex and involved that nothing seems beyond hope, that some refinement in method or the use of some selectively excreted substance, such as a dye or other foreign substance, may distinguish between the two conditions of vascular and parenchymal disturbance. The answer of our experiments is that the apparent similarity in the findings of the functional tests in the two cases is in fact an identity in the functional state in the two conditions though produced by different mechanisms; and there remains no reason to suppose that any procedure could distinguish between differences that in fact do not exist.

The observation of the anatomical changes in the kidneys of our experiments allowed on the other hand a ready determination of the significance of the alteration that existed in the two conditions of damage, since the fate of the organ could be predicted directly from the structural alterations observed. In our experiments the observations were made by histological means; other methods which have been shown by postmortem pathological evidence to be valid and to give similar information, are however available (7).

A final point in these experiments may be emphasized, well known perhaps, but often insufficiently appreciated, namely, a weakness in the anatomical approach to the problem. The morphologist is unable to describe even roughly the functional state of a kidney from its histological appearance. In certain cases of frank damage he may hazard a precarious guess, but severe functional disturbances may exist without any trace of structural derangement that can be seen by the eye. For all we know the converse may be true. And if such is the case in the simple and controlled conditions of our experiments, how can one venture to speculate on the significance or functional effects of inflamed glomeruli, abnormal tubules and sclerosed vessels as explaining some complicated clinical observation, the exact physiological basis of which is indeed unknown? Until the fundamental correlation of the two aspects of damage, functional derangement and structural change, has been made the whole problem of the abnormal kidney must remain not only unsolved but unsolvable.

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